The present invention relates to a technique with which a stable 3-alkenylcephem compound is prepared in a single step in which an unstable intermediate generated in the reaction system is reacted with a reagent at the same time. The resulting 3-alkenylcephem compound is useful as an intermediate of Cefixime that is a useful antibacterial agent having a wide range antibacterial spectrum disclosed in, for example, Handbook of Latest Antibiotics, 9th ed., Katsuji Sakai P. 83 (JP-B-20435/1988).
As a process for preparing 3-alkenylcephem compounds, it is generally employed, when taking 3-vinylcephem compounds as example, to conduct Wittig reaction with formaldehyde by using 3-chloromethylcephem derivative or 3-hydroxymethylcephem derivative as a starting material, as described in JP-B-20435/1988 and JP-A-263990/1986. In these processes, it is generally and widely employed that the reactions until phosphonium salt is obtained are conducted in one-pot and, after isolation of the phosphonium salt, ylidation is performed and the reaction with formaldehyde is resumed. In such a series of Wittig reaction, the respective compounds of iodide compound, phosphonium salt and ylide, each being intermediate, are often unstable, and thus it might be impossible to obtain a satisfactory yield. As a matter of fact, the reactions in JP-B-20435/1988 and JP-A-263990/1986 cause the problems that because of a temporal isolation of phosphonium salt, process is complicated and the total yield is low (the total yield of the former is 65%, and that of the latter is 52%). Further, both have many problems in practical production. For example, due to a low yield, by-products are formed in decomposition of the above-mentioned compounds. Accordingly, there has been a desire for an excellent reaction that is a short reaction step applicable industrially, and achieves a short residence time of unstable intermediates.
Process of JP-A-263990/1986: 
Alternatively, 3-vinylcephem compounds can be prepared by the reaction of allenyl xcex2-lactam compound with copper chloride/vinyltributyl tin or vinylcuprate, as described in Tetrahedron Lett., 1992, 33, 7029, and J. Org. Chem., 1994, 59, 4956. In either case, a large amount of copper salt is required, and a significant number of problems may arise with its industrial application from an environmental point of view. Further, since allenyl xcex2-lactam compound used in these reactions is unstable, there are also handling problems in a large scale reaction. 
In the meanwhile, there has been reported a process of preparing 3-vinylcephem compounds by subjecting a 3-trifluoromethane sulfonyloxycephem compound or 3-fluorosulfonyloxycephem compound to coupling reaction or reaction with vinyl cuprate, by using an organic tin compound/palladium catalyst. (Tetrahedron Lett., 1988, 29, Tetrahedron Lett., 1990, 31, 3389, 6043, Tetrahedron Lett., 1991, 32, 4073, and Journal of Organic Chemistry, 1990, 55, 5833). 
It is however difficult to industrially apply these processes because, when synthesizing a starting material, 3-trifluoromethanesulfonyloxycephem compound or fluoromethanesulfonyloxycephem compound is required to be prepared by using trifluoromethane sulfonic acid anhydride or fluorosulfonic acid anhydride, the industrial handling of which is difficult. It is also necessary to use an expensive palladium catalyst and copper reagent of not less than equivalent, in these reactions. Thus, there are a number of problems when these processes are put into practice.
Although the foregoing conventional techniques have been applied to not only a process for preparing 3-vinylcephem compounds but also 3-alkenylcephem compounds, there are essential problems remaining unsolved.
An object of the present invention is to provide a novel technique with which 3-alkenylcephem compounds can be prepared in a single easy handling with high yield, by using a 3-chloromethylcephem compound as a starting material, and simultaneously conducting reactions of iodization reagent, alkali metal hydroxide or carbonate, arylphosphine and aldehyde, to decrease the residence time of unstable intermediates in the system.
The present invention provides a process for preparing 3-alkenylcephem compounds characterized in that 3-alkenylcephem compound of the formula (3) is prepared in a single step by simultaneously conducting reactions of a 3-chloromethylcephem compound of the formula (1) with iodization reagent, alkali metal hydroxide or carbonate, arylphosphine and an aldehyde of the formula (2) 
wherein R1 is a hydrogen atom, halogen atom, amino group, protected amino group, or Arxe2x80x94CHxe2x95x90Nxe2x80x94 group where Ar is aryl group which may have a substituent; R2 is a hydrogen atom, halogen atom, lower alkoxy group, lower acyl group, lower alkyl group, lower alkyl group which has hydroxyl or protected hydroxyl as a substituent, hydroxyl group, or protected hydroxyl group; and R3 is a hydrogen atom or carboxylic acid protective group
R4xe2x80x94CHOxe2x80x83xe2x80x83(2)
wherein R4 is a hydrogen atom, or lower alkyl group which may have a substituent 
wherein R1, R2, R3 and R4 are as defined above.
With the conventional processes for preparing 3-alkenylcephem compounds by employing Wittig reaction, not only any satisfactory yield is obtained, but also it is time-consuming to purify the desired compound due to the by-product generated in the reactions. The inventor found that the reason for these was to allow unstable intermediates to reside for a long time during the isolation or in the system, and succeeded in preparing 3-vinylcephem compounds at high yield and purity when a reaction system for minimizing the residence time of such intermediates was discovered. Under the reaction conditions of the invention, the unstable intermediates react quickly with the reagents in the system, resulting in a 3-alkenylcephem compound. Therefore, examples of cephem compounds, the existence of which is recognizable in the system, are stable 3-chloromethylcephem compounds and 3-alkenylcephem compounds.
The wavy line bonded to R4 of the formula (3) of the invention denotes a stereoisomer and means that against the double bond of 3-alkenyl group, R4 is cis alone, trans alone, or a cis/trans mixture.
Examples of the groups described in the present specification are as follows:
Halogen atom means fluorine, chlorine, bromine, iodine, or the like.
Lower alkyl group means, for example, a straight-chain or branched C1xcx9cC4 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Aryl group means, for example, phenyl, anisyl or naphthyl.
Examples of the protected amino group represented by R1 are formamido, phenoxyacetamido, p-methylphenoxyacetamido, p-methoxyphenoxyacetamido, p-chlorophenoxyacetamido, p-bromophenoxyacetamido, phenylacetamido, p-methylphenylacetamido, p-methoxyphenylacetamido, p-chlorophenylacetamido, p-bromophenylacetamido, phenylmonochloroacetamido, phenyldichloroacetamido, phenylhydroxyacetamido, phenylacetoxyacetamido, xcex1-oxophenylacetamido, thienylacetamido, benzamido, p-methylbenzamido, p-t-butylbenzamido, p-methoxybenzamido, p-chlorobenzamido, p-bromobenzamido, etc. In addition to these, there are the groups disclosed in xe2x80x9cProtective Groups in Organic Synthesis written by Theodora W. Greene, 1981, by John Wiley and Sons. Inc.xe2x80x9d (hereinafter referred to merely as the xe2x80x9cliteraturexe2x80x9d), Chap. 7 (pp. 218-287), and phenylglycylamido, phenylglycylamido in which amino group is protected, p-hydroxyphenylglycylamido, and p-hydroxyphenylglycylamido in which either of amino and hydroxyl, or both of these are protected. Examples of protective groups for the amino of phenylglycylamido group and p-hydroxyphenylglycylamido group are those disclosed in the literature, Chap. 7 (pp. 218-287). Examples of protective groups for the hydroxyl of p-hydroxyphenylglycylamido are those disclosed in the literature, Chap. 2 (pp. 10-72).
Examples of the aryl of Arxe2x80x94CHxe2x95x90Nxe2x80x94 group are phenyl and phenyl groups which may have a substituent, such as p-methoxyphenyl, p-nitrophenyl and m-hydroxyphenyl.
Exemplary of the substituent which may be substituted in the aryl represented by Ar are halogen atom; hydroxyl; nitro; cyano; aryl; lower alkyl; amino; mono-lower alkylamino; di-lower alkylamino; mercapto; alkylthio or arylthio represented by group R7Sxe2x80x94 (R7 is a lower alkyl or aryl); formyloxy; acyloxy represented by group R6COOxe2x80x94 (R6 is hydrogen atom, lower alkyl, or aryl); formyl; acyl represented by group R6COxe2x80x94 (R6 is as defined above); alkoxy or aryloxy represented by group R6Oxe2x80x94 (R6 is as defined above); carboxyl; and alkoxylcarbonyl or aryloxycarbonyl represented by group R6OCOxe2x80x94 (R6 is as defined above). The aryl represented by Ar is substituted by substituents of the same or different kinds selected from among the above substituents, and at least one substituent may be substituted in the same or different carbon.
Examples of the lower alkoxy represented by R2 are straight-chain or branched C1xcx9cC4 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
Examples of the lower acyl represented by R2 are straight-chain or branched C1xcx9cC4 acyl groups such as formyl, acetyl, propionyl, butyryl and isobutyryl.
Examples of protected hydroxyl groups for lower alkyl represented by R2 and substituted with hydroxyl group or protected hydroxyl group, and examples of protective groups for the protected hydroxyl represented by R2, are those disclosed in the literature, Chap. 2 (pp. 10-72). The above lower alkyl groups represented by R2 is substituted by substituents of the same or different kinds selected from among hydroxyl group and the protected hydroxyl groups as defined above, and at least one of such substituents may be substituted in the same or different carbon.
Exemplary of the carboxylic acid protecting groups represented by R3 are benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, trichloroethyl, tert-butyl, or the groups described in the literature, Chap. 5 (pp. 152-192).
Exemplary of the lower alkyl groups which may have a substituent represented by R4 are straight-chain lower alkyl groups such as methyl, ethyl and propyl; branched lower alkyl groups such as isopropyl and isobutyl; and halogenated lower alkyl groups such as chloromethyl and bromomethyl. Besides these, it is possible to use the lower alkyl groups having a substituent which may be substituted in the aryl represented by the above Ar.
In the present invention, 3-chloromethylcephem compounds of the formula (1), which are used as a starting material, are prepared by, for example, the method described in literature [(Torii et al., Tetrahedron Lett., 23, pp. 2187-2188 (1982)].
In accordance with the present invention, a 3-chloromethylcephem compound of the formula (1) to be prepared by the above method is reacted with, for example, triphenylphosphine and formaldehyde in the presence of iodization reagent and alkali metal hydroxide or carbonate, thereby obtaining a 3-vinylcephem compound of the formula (2).
Examples of iodization reagents are alkali metal iodide salts such as lithium iodide, sodium iodide and potassium iodide; alkaline earth metal iodide salts such as calcium iodide; ammonium iodide; and quaternary ammonium iodide salts such as tetraethyl ammonium iodide. These iodization reagents can be used singly or in a combination of at least two of them. These iodization reagents are usually used in an amount of one to three moles, preferably one to two moles, per mole of the compound of the formula (1). These iodization reagents can be used in the form of an aqueous solution.
Examples of alkali metal hydroxide or carbonate are lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate. These alkali metal hydroxides or carbonates can be used singly or in a mixture of at least two of them. These alkali metal hydroxides or carbonates are usually used in an amount of one to ten moles, preferably one to three moles, per mole of the compound of the formula (1). These alkali metal hydroxides or carbonates can be used in the form of an aqueous solution.
As the arylphosphine used in the present invention, there are triphenylphosphine which may have a substituent, such as triphenylphosphine and tri-p-methoxyphenylphosphine. As the groups that can be substituted for phenyl, it is possible to use the substituents which may be substituted for the aryl represented by the above Ar. Triarylphosphine is usually used in an amount of one to five moles, preferably one to three moles, per mole of the compound of the formula (1).
Examples of aldehydes of the formula (2) used in the present invention are straight-chain or branched lower alkylaldehydes which may have a substituent, such as formaldehyde, acetaldehyde, chloroacetaldehyde and isobutylaldehyde; and arylaldehydes which may have a substituent, such as benzaldehyde, tolylaldehyde and anisaldehyde. As the substituent that may be substituted for lower alkyl and aryl, it is possible to use all the substituents that may be substituted for the aryl represented by the above Ar. The aldehyde of the formula (2) is usually used in an amount of 1 to 30 moles, preferably 1 to 15 moles, per mole of the ccmpound of the formula (1). It is not particularly required to use the aldehyde of the formula (2) in gaseous form, or use the aldehyde anhydride. The aldehyde in the form of an aqueous solution is also usable.
Examples of solvents are ketones such as acetone; ethers such as tetrahydrofuran (THF) and dioxane; hydrocarbon halides such as methylene chloride and chloroform; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile and valeronitrile; and dimethyl sulfoxide. These can be used singly or in a mixture of at least two of them. Alternatively, it is possible to use a mixed solvent in which the above solvent is used mainly and other usual solvents are added thereto. As the usual solvents, there are, for example, lower alkyl esters of lower carboxylic acids such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate and ethyl propionate; ethers such as diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methylcellosolve and dimethoxyethane; cyclic ethers such as tetrahydrofuran and dioxane; substituted or unsubstituted aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and anisole; hydrocarbons such as pentane, hexane, heptane and octane; cycloalkanes such as cyclopentane, cyclohexane, cycloheptane and cyclooctane; and halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride and carbon tetrachloride. Particularly preferred solvent are mixed solvents of which main solvent is dimethylformamide, 1-methyl-2-pyrrolidinone or dimethyl sulfoxide. The above solvents are not required to be anhydrous, and hydrous solvents are also usable.
These solvents are used in an amount of about 0.5 to 200 liter, preferably about 1 to 50 liter, per 1 kg of the compound of the formula (1).
The reaction is conducted in the range of xe2x88x9210 to 80xc2x0 C., preferably 0 to 50xc2x0 C.
The compound of the formula (2) can be obtained as an approximately pure product, by performing, after the reaction is terminated, the usual extraction or crystallization. It is, of course, possible to purify by any other method.
Suitable solvents are mixed solvents corprising mainly dimethylformamide, 1-methyl-2-pyrrolidinone or dimethyl sulfoxide. These solvents are not required to be anhydrous, and hydrous solvents are also usable.